Project Summary The goal of this R03 application is to identify markers for apical periodontitis (AP) in humans. AP represents a local immune response to the progression of microorganisms from an infected root canal space to the periapical area that results in bone resorption and affects ~27% of the general population. Recent studies have shown that genetic predisposition can contribute to an individual's susceptibility to developing AP, and that a complex signaling network operates in the determination of the nature and extent of AP progression, as well as the associated bone destructive process. Using traditional candidate gene discovery approaches, we have shown that common variants in matrix metalloproteinases, interleukins and heat shock protein genes were associated with AP. However, the genetic factors influencing apical periodontitis susceptibility have not yet been thoroughly investigated. To establish the role of genetic predisposition in the etiology of AP, in this proposal, we will perform a genome-wide association study to identify common genetic variants associated with AP risk on ~1,000 cases and controls with and without AP. We will validate the 10 top associated variants in an independent validation population, and will identify genetic risk signatures that may facilitate identification of individual predisposition to AP. Results from this study will help us understand genetic factors contributing to AP in humans, dramatically increasing knowledge of the condition and providing insights into the future development of therapeutic targets.